Pharmaceutical compositions

ABSTRACT

The present invention provides a pharmaceutical composition for the transdermal systemic administration of an active agent characterized in that the active agent is bopindolol or methysergide. Also the present invention provides a pharmaceutical composition for the transdermal systemic administration of a pharmacologically active agent characterized in that it contains bopindolol, tizanidine, clemastine, ketotifen or methysergide as active agent in a reservoir comprising a hydrophilic polymer. Furthermore a pharmaceutical composition for the transdermal systemic administration of pharmacologically active agents characterized in that the pharmacologically active agent is in a reservoir comprising a polyacrylate polymer containing cationic ester groups.

This is a continuation of application Ser. No. 08/141,832, filed Oct.22, 1993 now U.S. Pat. No. 5,364,628, which in turn is a continuation ofapplication Ser. No. 07/804,630, filed Dec. 9, 1991, which in turn is acontinuation of application Ser. No. 07/597,470, filed Oct. 3, 1990which in turn is a continuation of application Ser. No. 07/298,457,filed Jan. 18, 1989, which in turn is a continuation of application Ser.No. 07/096,571, filed Sep. 3, 1987, which in turn is a continuation ofapplication Ser. No. 06/740,917, filed as PCT/EP85/00061, Feb. 21, 1985,the later five of which are now abandoned.

This invention relates to pharmaceutical compositions, especially forthe systemic transdermal administration of pharmacologically activeagents.

Many pharmaceutical compositions have been proposed for the sustainedtransdermal administration of pharmacologically active agents into thesystemic circulation. These generally comprise essentially a solidreservoir or matrix made of a solid polymer or gel containing thepharmacologically active agent dispersed throughout. On one side of thedrug reservoir there is a backing member impermeable to the drug and onthe other side a protective peel strip which is taken off before use.The backing member may be larger than the drug reservoir and may carrynear its edges an adhesive layer to retain the protective peel stripand, when this is removed, to stick the unit to the skin. Additionallyor alternatively a drug-permeable adhesive layer may be provided on thereservoir to retain the protective peel strip and stick the unit to theskin. In some proposals the drug reservoir has attached to it adrug-permeable control membrane or member, through which thepharmacologically active agent passes, in order to regulate the rate ofpassage of the active agent, e.g. to prevent dose dumping.

In use after the peel strip has been removed, the unit is stuck into theskin and the pharmacologically active agent passes from the drugreservoir to the skin. More complicated systems have been proposed toimprove the penetration rate of the pharmacologically active agentthrough the skin. However, most systems do not provide a sufficientpenetration rate of the pharmacologically active agent or suffer fromother disadvantages. Before the priority date of the present applicationthe transdermal pharmaceutical compositions for systemic administrationof drugs commercially available on a wide scale were restricted topharmacologically active agents which exist in liquid form e.g.scopolamine or nitroglycerin, and which in any event easily penetratethe skin.

There is thus a need for new approaches to the transdermal applicationof solid and liquid pharmacologically active agents using controlledrelease systms.

We have now surprisingly found that the pharmacologically active agentbopindolol, 4-(2-benzoyloxy-3-tert-butylaminopropoxy)-2-methylindole, abeta-blocker which is known for oral administration e.g. for thetreatment of hypertension, and methysergide(9,10-didehydro-N-[1-(hydroxymethyl)propyl]-1,6-dimethylergoline-8-carboxamide, a known serotonin antagonist e.g.for the prophylaxis of migraine, have especially interesting propertiesfor transdermal administration. These are hereinafter referred to as theactive agents of the invention.

The penetration of these active agents through the skin may be observedin standard in vitro or in vivo tests.

One in vitro test is the well known diffusion test which may be effectedaccording to the principles set out in GB 2098865 A and by T. J. Franzin J. Invest. Dermatol (1975) 64, 194-195. Solutions containing theactive agent in unlabelled or radioactively labelled form are applied toone side of isolated pieces of intact human skin or hairless rat skinabout 2 cm² in area. The other side of the skin is in contact withphysiological saline. The amount of active agent in the saline ismeasured in conventional manner, e.g. by HPLC or spectrophotometrictechniques, or by determining the radioactivity.

Typically using rat skin a penetration flux of from 0.1 to 10microgram/cm² /hour over 24 hours is observed for the active agents.

In one aspect the present invention provides a method of systemicallyadministering the active agent bopindolol or methysergide whichcomprises administering the active agent to the skin. In a furtheraspect the present invention provides the use of bopindolol ormethysergide as active agent in the manufacture of a medicament suitablefor systemic transdermal administration. In a further aspect the presentinvention provides a pharmaceutical composition for the transdermalsystemic administration of an active agent characterised in that theactive agent is bopindolol or methysergide.

In general for application e.g. behind the ear an amount of bopindololor methysergide from about 1 to 6 mg is indicated, e.g. 5 mg for a dosefor 1 to 3 days.

The active agents of the invention may be administered in anyconventional liquid or solid transdermal pharmaceutical composition,e.g. as described in Remington's Pharmaceutical Sciences 16th EditionMack; Sucker, Fuchs and Spieser, Pharmaceutische Technologie 1stEdition, Springer and in GB 2098865 A or DOS 3212053 the contents ofwhich are incorporated herein by reference. Conveniently the compositionis in the form of a viscous liquid, ointment or solid matrix. The activeagent may be incorporated in a plaster.

We have now found that the above active agents, bopindolol andmethysergide, as well as the following pharmacologically active agentstizanidine, ketotifen and clemastine may be advantageously administeredtransdermally from a drug reservoir comprising a hydrophilic polymerhaving the pharmacologically active agent dispersed throughout.

Tizanidine, ketotifen and clemastine have previously been disclosed fortransdermal administration. GB 2098865 A discloses topicalmicroemulsions containing these pharmacologically active agents Themicroemulsions are to be applied to the skin as a cream.

Tizanidine is a known myotonolytic agent e.g. for the treatment of localmuscle spasms e.g. rheumatic pains and spastic conditions. Ketotifen andclemastine are anti-histamines e.g. for the treatment of allergicconditions. Ketotifen also is an anti-anaphylatic agent, e.g. for theprophylaxis of asthma.

In a further aspect the present invention provides a pharmaceuticalcomposition for the transdermal systemic administration ofpharmacologically active agents characterised in that it containsbopindolol, tizanidine, clemastine, ketotifen or methysergide in areservoir comprising a hydrophilic polymer. In yet a further aspect thepresent invention provides the use of these active agents in ahydrophilic polymer for the manufacture of a transdermal medicamentsuitable for systemic administration of the active agent through intactskin.

The hydrophilic polymers take up water and are permeable to water, e.g.moisture from the skin, although the polymers may be insoluble in water.The polymers may swell and provide release of a large amount ofpharmacologically active agent leading to a high concentration gradientof pharmacologically active agent between the skin surface and stratumcorneum at a pH of from 4 to 7, preferably at skin pH, e.g. 5.5. Ifdesired they may be soluble in organic solvents. Examples of suitablepolymers include polyacrylamide and its co-polymers,polyvinylpyrrolidone (PVP), vinyl acetate/vinyl alcohol co-polymers,polyvinyl alcohol (PVA) and derivatives, ethyl cellulose and othercellulose and starch derivatives.

The polymer preferably has a mean molecular weight of from about 50,000to about 300,000 Daltons, such as 100,000 to 200,000 Daltons, and ispreferably film forming.

Hydrophilic polyacrylates are preferred polymers. The acrylate may besubstituted, e.g. a methacrylate. They may be commercially availableacrylate/methacrylate co-polymers. Some or all of the acid groups may beesterified, e.g. with alkyl groups such as methyl or ethyl groups.Preferably at least 2% of the alkyl groups may contain polarsubstituents, e.g. a hydroxy group.

It has been found that polyacrylates containing cationic functionalgroups are especially preferred.

Transdermal pharmaceutical compositions for the systemic administrationof pharmacologically active agents through intact skin wherein theactive agent is in a reservoir comprising a polyacrylate containingcatonic functional groups are novel and form part of the presentinvention.

The present invention also provides the use of a pharmacologicallyactive agent in a polyacrylate containing cationic groups for themanufacture of a medicament suitable for transdermal systemicadministration of the pharmacologically active agent through intact skinof a subject. In another aspect the present invention provides a methodof systemically administering a pharmacologically active agent to asubject which comprises contacting a reservoir of the pharmacologicallyactive agent in a polyacrylate containing cationic ester groups tointact skin.

Examples of cationic groups include dialkylaminoalkyl groups, e.g.dimethyl aminoalkyl groups.

Especially preferred cationic groups include quaternary ammonium groups,preferably a tri(alkyl)aminoalkyl group. Examples of such groups aretrimethylaminoethyl ester groups.

The polyacrylate may contain some carboxylic acid groups in free form orsalt anions, e.g. chloride anions in order to balance the cationicgroups.

The ratio of cationic groups to neutral groups is preferably from 1:10to 1:50 e.g. from 1:20 to 1:40.

Preferably the polymers have an alkali count (defined in analogousmanner to acid count) of from about 10 to about 200 mg KOH per grampolymer, e.g. 10 to 30 mg KOH per gram polymer.

Examples of commercially available polymers of this type include:--

1) Polymers of acrylate and methacrylate esters containing methyl andethyl neutral ester groups and trimethylaminoethyl cationic estergroups. Chloride ions are present. Mean Molecular weight 150000 Daltons.Viscosity (20° C.), maximum 15 cP. Refractive index 1.380-1.385. Density0.815-0.835 g/cm³. Ratio of cationic ester groups to neutral alkylgroups 1:20 giving an alkali count of 28.1 mg KOH per gram polymer(Eudragit RL 100 Registered Trade Mark available from Rohm, Darmstadt,W. Germany) or 1:40 giving an alkali count of 15.2 mg KOH per grampolymer (Eudragit RS 100 Registered Trade Mark, also available fromRohm).

2) Polymer of methacrylate esters containing trimethylaminoethylcationic ester groups and other neutral (C₁₋₄)alkyl ester groups.Chloride ions are present. Mean molecular weight 150,000. Viscosity (20°C.) 10 cP. Refractive Index 1.38. Density 0.815. Alkali number of 180 mgKOH per gram polymer (Eudragit E 100, Registered Trade Mark, alsoavailable from Rohm).

The drug reservoir may contain plasticizers and/or softeners preferablyskin compatible tensides e.g. to provide flexibility to the unit, and/orto dissolve partially or totally the pharmacologically active agent inthe reservoir.

Examples of additives include:--

1) Polyoxyethylene fatty alcohol ethers. The alcohol may e.g. be aC₁₂₋₁₈ alcohol. The HLB value may be e.g. from 10 to 18. A preferredexample is polyoxyethylene-(10) oleyl ether. A suitable ether may have aviscosity (25° C.) of about 100 cP, a solidification point of about 16°C., an HLB value of 12.4 and an acid count maximum 1.0 (Brij 97Registered Trade Mark available from Atlas Chemie W. Germany).

2) Polyoxyethylene Sorbitan fatty acid esters. The fatty acid may bee.g. a C₁₂₋₁₈ fatty acid. The HLB value may be e.g. from 10 to 18. Apreferred example is polyoxyethylene-(20) sorbitan monooleate, e.g.Tween 80, Registered Trade Mark available from Atlas Chemie, W. Germany.

3) Polyoxyethylene-(5-40) stearic acid esters, e.g. Myrj (RegisteredTrade Mark) available from Atlas Chemie, W. Germany.

4) Polyoxyethylene glycol fatty alcohol ethers, e.g. polyethyleneglycol-(6-25) cetyl ether, glycerin polyethylene ricinoleate, glycerinpolyethylene glycol stearate (Cremophor brand, Registered Trade Markavailable from BASF W. Germany).

5) Polyoxyethylene glycols of MW from 200 to 600 Daltons, e.g. 300 or400 Daltons.

6) Esters of poly(2-7)ethylene glycol glycerol ether having at least onehydroxyl group and an aliphatic (C₆₋₂₂) carboxylic acid, e.g.Polyethylene glycol-(7) glyceryl cocoate, e.g. Cetiol HE, RegisteredTrade Mark, from Henkel, W. Germany.

7) Adipic acid lower alkyl esters, e.g. di-n-butyl adipate anddiisopropyl adipate.

8) Glycerin polyethylene glycol ricinoleate e.g. Product of 35 molesethylene oxide and castor oil e.g. Brand Chremophor EL Registered TradeMark, obtainable from BASF, W. Germany.

9) Triacetin-(1,2,3).

The amount and type of additive required will depend on a number offactors, e.g. the HLB value of the tenside and the flexibility of theunit required. Surprisingly the amount of additive does notsignificantly influence the capability of the polyacrylate to formfilms. Generally the weight ratio of tenside to the hydrophilic polymeris from about 1:10 to 5:1, e.g. 1:10 to 1:3.

The drug reservoir may contain skin penetration promoters, e.g.1-dodecylazacycloheptan-2-one(azone) and N,N-diethyl-m-toluamide (DEET).

The amount and type of skin penetration promoter, and/or additivespresent will depend on a number of factors. Generally the weight ratioof skin penetration promoting agent to hydrophilic polymer will be fromabout 1:1 to 1:10. Preferably the amount of tenside and/or skinpenetration promoter is from about 3 to about 50%, preferably 20 to 40%by weight of the pharmaceutical composition.

If desired the drug reservoir may contain a hydrophobic elastomer, e.g.a synthetic resin. Such resins are conventional in the plaster art.Suitable resins include non-swellable acrylate resins. These may ifdesired be adhesive. The weight ratio of hydrophilic polymer to resinmay for example be from 1:0.5 to 1:10. The resin may contain modifiers,extenders, e.g. of softening point about 50° to 100° C. Such extendersmay have adhesive or softening properties. Examples of such extendersinclude resin acids, glyceryl and phthalate esters of resin acids,hydrogenated abietyl alcohol and its phthalate esters. The extenders forexample be present in an amount of from 5 to 40% of the weight of theresin.

Any pharmacologically active agent capable of penetration of the skinmay be dispersed throughout the hydrophilic polymer. The indication forwhich the active agent is used is not critical. It is preferred that thedaily transdermal dose for such agents is less than 20 mg per day, e.g.less than 10 mg per day.

The active agent for use in any of the pharmaceutical compositionsmentioned above may be in free form e.g. free base form or inpharmaceutically acceptable salt form e.g. pharmaceutically acceptableacid addition salt form.

Such acid addition salt forms include the hydrogen malonate, hydrogenmaleate, hydrogen fumarate, hydrochloride, tartrate etc. Preferably asolid active agent has an average particle diameter of from about 30 toabout 50 microns. The active agent may be partly suspended and/or partlydissolved in the reservoir. It may be dispersed so finely that to theeye a smooth homogenous film results.

The pharmaceutical compositions of the invention are useful for thesystemic administration of pharmacologically active agents throughintact skin, as indicated in standard in vitro and in vivo tests.

The release of active agent from the pharmaceutical compositions may befollowed for example by determining e.g. by ultraviolet spectroscopy,the amount of active agent released on shaking the pharmaceuticalcomposition in 0.9% NaCl solution at 37° C. at a paddle speed of about120 rpm.

The penetration of the active agent through isolated rat and human skinmay be followed in the well known diffusion test effected according tothe principles, e.g. set out in GB 2098865 A and in T. J. Franz, J.Invest. Dermatol (1975), 64, 191-195. The pharmaceutical compositions ofthe invention are applied to the external side of isolated rat or humanskin pieces about 2 cm² in area. The rat skin is hairless. The otherside is continuously washed with physiological saline. The amount ofactive agent in the saline is determined in conventional manner, e.g.HPLC. The penetration flux over 24 hours may then be ascertained, and ifdesired the steady state flux. The penetration flux rate is in the orderof 1 to 10 micrograms/cm² /hour. Alternatively the penetration of theactive agent may be followed in vivo by applying the pharmaceuticalcomposition to intact skin, e.g. on the chest, back, arm or behind theear, of a subject and measuring the amount of active agent in the blood.

The pharmaceutical compositions of the invention may be used for thesame indications as known for oral or intravenous administration. Theamount of pharmaceutically active agent to be administered willindividually depend on the drug release characteristics of thepharmaceutical compositions, the drug penetration rate observed in invitro and in vivo tests, the potency of active agent, the size of theskin contact area, the part of the body to which the unit is stuck, andthe duration of action required. The amount of active agent and area ofthe pharmaceutical composition etc may be determined by routinebioavailability tests comparing the blood levels of active agents afteradministration of the active agent in a pharmaceutical compositionaccording to the invention to intact skin and blood levels of activeagent observed after oral or intravenous administration of atherapeutically effective dose of the pharmacologically active agent.

Given the daily dose of a drug for oral administration, the choice of asuitable quantity of drug to be incorporated in a transdermalcomposition according to the invention will depend upon thepharmacokinetic properties of the active agent, including the first passeffect; the amount of drug which can be absorbed through the skin fromthe matrix in question for a given area of application and in a giventime; and the time for which the composition is to be applied. Thus, adrug with a high first pass effect may require a relatively low quantityin the transdermal composition when compared with the oral daily dose,since the first pass effect will be avoided. On the other hand,generally a maximum of only approx. 50% of the drug in the matrix isreleased through the skin in a 3 day period.

The pharmaceutical compositions of the invention in general have forexample an effective contact area of drug reservoir on the skin of fromabout 1 to about 50 square centimeters, preferably about 2 to 20 squarecentimeters, and are intended to be applied for from 1-7 days,preferably 1-3 days.

Examples of representative doses

    ______________________________________                                        1) Tizanidine                                                                           A dose of 20 mg in a patch of ca 10 cm.sup.2 to be                            administered once every 3 days for the systemic                               treatment of rheumatic pains and muscle spasms.                     2) Bopindolol                                                                           A dose of 1 to 10 mg in a patch of 10 cm.sup.2 to be                          administered once over 3 consecutive days in                                  each week for treatment of hypertension.                            3) Clemastine                                                                           A dose of about 1 to 20 mg in a patch of ca 10                                cm.sup.2 to be administered once every 3 days for                             treatment of allergies, eg. hay fever.                              4) Ketotifen                                                                            A dose of about 1 to 20 mg in a patch of ca 10                                cm.sup.2 to be administered once every 3 days for                             prophylaxis of asthma.                                              5) Methysergide                                                                         A dose of about 1 to 10 mg in a patch of ca 10                                cm.sup.2 to be administered once every 3 days for                             prophylaxis of migraine and migraine interval                                 treatment.                                                          ______________________________________                                    

The pharmaceutical compositions of the invention may be produced inconventional manner by dispersing or dissolving an appropriatepharmacologically active agent through a hydrophilic drug reservoir.

The weight ratio of pharmacologically active agent to hydrophilicpolymer may vary between wide limits. The weight ratio may be forexample sufficient to produce a supersaturation of the pharmacologicallyactive agent in the drug reservoir. In general the weight ratio is fromabout 1:10 to about 1:1.

For example in the case of tizanidine the amount may be for example from10 to 40 percent, e.g. 15 to 30 or 20 to 25 percent, by weight.

If the drug reservoir is not itself adhesive a pressure sensitiveadhesive may be used to stick the drug reservoir to intact skin. Anyconventional adhesive may be used, e.g. a polyacrylate. The layer may beapplied to the drug reservoir and have a thickness of from about 1 toabout 200 microns preferably 10 to 100 microns. If the adhesive layer isthin enough then the pharmacological agent will pass through it.Alternatively the adhesive layer may be applied to the edges of an outercover for the drug reservoir and the outer cover stuck to the intactskin holding the drug reservoir in close contact with the intact skin.

The drug reservoir may be produced in conventional manner, e.g. in anadhesive plaster or patch. If it is a polymer matrix it may be producedby dispersing or dissolving the pharmacologically active agent in asolution of the polymer and other additives in a volatile organicsolvent, e.g. ethanol, methylene chloride, or acetone. A film is formedby spreading the dispersion or solution over the outer protective cover.The wet film may have a thickness of about 0.05 to 0.5 millimeters, e.g.0.1 to about 0.3 millimeters. The film is allowed to dry, e.g. at roomtemperature or a slightly elevated temperature below 50° C. The drugreservoir may be built up in a series of layers and then any adhesivelayer provided in the last layer.

BRIEF DESCRIPTION OF THE DRAWINGS

The pharmaceutical compositions of the invention may be produced inconventional manner for skin penetration pharmaceutical compositions.FIG. 1 of the accompanying drawings gives a schematic cross-sectionthrough the layers of a representative pharmaceutical compositionaccording to the invention. FIG. 2 of the accompanying drawings gives aschematic cross-section of a another embodiment, e.g. in the form of abandage or plaster. In FIGS. 1 and 2 there are several layers a-d and inthe case of FIG. 2, additionally layer e. Layer a is a medical covermade out of e.g. polyester/aluminium laminate foil. Layer b is anocculsive foil, e.g. of aluminium foil. If desired this may be omitted.Layer c may be made out of 1 to 10 layers of a drug reservoir. The drugreservoir is a homogenous dispersion of active agent particles or asolution of active agent in a polymer matrix. Layer d may be an adhesivelayer. In one embodiment (not shown) the layer d may extend to betweenthe outer edges of layer a and layer e. Alternatively the layer e may beomitted completely, Layer a may extend around layers b to d in FIG. 2.Layer e is a protective peel off layer which is stuck to the adhesivelayer as well as to the edges of the cover layer a.

On use any protective layer e is peeled off and the unit stuck to intactskin.

In the following examples all temperatures are in degrees Centigrade andare uncorrected. All amounts are in parts by weight unless otherwisestated.

Details of components are given in Lexicon for Pharmazie, Kosmetic andangrenzende Gebiete by H. P. Fiedler, 2 Edition, Cantor Aulendorf, W.Germany or from the relevant manufacturers.

In the following examples, the indicated terms have the meaning shownbelow:--

PAM Amine polymer RL: Polyacrylate/methacrylate cationic polymer asdefined above under the term EUDRAGIT RL 100.

PAM Amine polymer RS: Polyacrylate/methacrylate cationic polymer asdefined above under the term EUDRAGIT RS 100.

PAM Amine polymer E: Polymethacrylate cationic polymer as defined aboveunder the term EUDRAGIT E 100.

Polyoxyethylene(10) oleyl ether: BRIJ 97 as defived above. GlycerinPolyethylene glycol(35)-ricinoleate=Cremophor EL as defined above.

Polyoxyethylene(20) sorbitan monooleate=Tween 80 as defined above.

Polyethylene(7) glycol glyceryl cocoate=Cetiol HE as defined above.

Acrylate synthetic resin is self cross-linking acrylate Brand Durotack280-2416 available from Delft National Chemie Zutphen Netherlandsavailable as a light yellow solution containing as solvent 57% ethylacetate, 32% ethanol, 9% hexane, 2% methanol: solids content 41%,Viscosity (Brookfield)=2100-6000 mPas, Plasticity (Williams)±3 mm,Density 0.94 Flashpoint 0.94.

EXAMPLE A

Preparation of pharmaceutical composition containing a hydrophilicpolymer

    ______________________________________                                        Composition                                                                   Pharmacologically active agent                                                                     20%                                                      Hydrophilic polymer  40%                                                      Tenside              40%                                                      ______________________________________                                    

1.2 g of hydrophilic polymer are dissolved in 3 g acetone or ethanol orother appropriate volatile organic solvent with stirring in 1 to 2hours. 0.6 g pharmacologically active agent and 1.2 g of tensidesoftener are added. The mixture is vigorously stirred for about 5 to 20minutes with a high speed stirrer to give a viscous mass.

The mass is spread as a film on top of an aluminised polyester foil(thickness 23 microns) using a conventional apparatus, e.g. an Erichsenfilm apparatus Model 411/150. The mass is spread across the foil at aspeed of 18 mm/sec to produce a film of thickness 0.2 mm when wet.

The film is allowed to dry at room temperature over 4 to 6 hours. Theresultant hydrophilic polymer drug matrix weighs 8.5 mg per squarecentimeter and contains 1.7 mg active agent per square centimeter.

A further film of an acrylate adhesive (Rohm Pharma 7708/47) is thenapplied onto the drug polymer matrix as a thin layer (0.1 mm thickness)in analogous manner.

The aluminium foil is then cut up into patches about 10 sq cm in area.

Unless otherwise stated the drug matrix is built up from one film layer.It may if desired be built up as more than one layer.

The release of active agent is measured in vitro in standard skindiffusion tests through freshly isolated hairless rat skin. The rat skinpiece is located in a Franz diffusion chamber--see T. J. Franz, J.Invest. Dermatol 1975 (64) 191-195. The receptor phase is pumpedcontinuously and every hour samples are taken and measured for activeagent content using HPLC. The trial lasts 24 hours and the penetrationflux over 24 hours (hereinafter referred to as "flux") and if desired asteady state flux after a lag time of 3 to 10 hours is measured.

EXAMPLE 1 Tizanidine Composition

Prepared as disclosed in Example A with a composition of

    ______________________________________                                        Tizanidine hydrochloride                                                                           20%                                                      PAM Amine Polymer RL 40%                                                      Polyoxyethylene-10 oleyl ether                                                                     40%                                                      ______________________________________                                    

Active agent penetration rate in rat skin:

Penetration Flux±=0.0145 mg/cm² /hr

Total penetration±=0.290 mg/cm² ca 21.46%

Remainder detected in plaster ca 47%

EXAMPLE 2 Tizanidine Composition

Prepared in analogous manner to that described in Example A with acomposition of

    ______________________________________                                        Tizanidine hydrochloride                                                                           1.144 g                                                  PAM Amine polymer RL 1.928 g                                                  Polyoxyethylene-10 oleyl ether                                                                     1.928 g                                                  ______________________________________                                    

The active agent is dissolved in 5 g ethanol as solvent. Spreading speed6 mm/sec. Thickness of wet film 0.25 mm. Concentration of active agentin film 2.6 mg/cm² No adhesive acrylate film is present.

Active agent penetration rate through rat skin:

Penetration Flux=8.5 microgram/cm² /hr

Steady state flux=16.2 microgram/cm² /hr

In a clinical trial a 2 cm² patch of the composition is applied to theleft underarm and after 12, 24 and 36 hours the remaining tizanidinecontent in the patch determined.

Flux rate=5.1 microgram/cm² /hr

EXAMPLE 3

Prepared as described in Example 2 using as solvent methylene chlorideinstead of ethanol. Composition:

    ______________________________________                                        Tizanidine hydrochloride                                                                           1.144 g                                                  PAM Amine polymer RL 1.928 g                                                  Polyoxyethylene-10 oleyl ether                                                                     1.628 g                                                  Triacetin (1, 2, 3)  0.250 g                                                  ______________________________________                                    

Penetration rate through rat skin: Penetration Flux 10.4 microgram/cm²/hr

In a clinical trial a 2 cm² patch was applied as in Example 2.Penetration Flux 4.9 microgram/cm² /hr

EXAMPLE 4 Tizanidine Pharmaceutical Composition

Prepared in analogous manner to that disclosed in Example 2. Spreadingspeed=18 mm/sec Thickness of wet film: 0.2 mm Concentration of activeagent: 1.7 mg/cm² An acrylate film adhesive layer is applied as inExample A.

Penetration rate through rat skin. Penetration Flux=14.5 microgram/cm²/hr Steady state Flux=30.8 microgram/cm² /hr

EXAMPLE 5 Tizanidine Pharmaceutical Compositions

The tenside in Example 2 is replaced by an equivalent amount of

i) Polyethylene glycol 300

ii) Glycerin polyethylene glycol-(35) ricinoleate

iii) Polyoxyethylene-(20) sorbitan monooleate

iv) azone and/or PAM Amine polymer RL is replaced by PAM Amine polymerRS or PM Amine polymer E.

EXAMPLES 6-8 Clemastine Pharmaceutical Compositions

The following compositions are made in analogous manner to Example 2.

    ______________________________________                                        Example           6        7        8                                         ______________________________________                                        Clemastine hydrogen fumarate                                                                    1      g     1.34 g   1    g                                PAM Amine polymer RL                                                                            2      g     --       --                                    PM Amine polymer E                                                                              --     g     2.41 g   2.66 g                                Polyoxyethylene (10) oleyl ether                                                                2      g     1.25 g   --                                    Polyethylene glycol 300                                                                         --           --       1.34 g                                Solvent           Acetone  Acetone  CH.sub.3 OH                               Solvent amount (g/g dry film)                                                                   0.6      0.5      2.0                                       Thickness of wet film (mm)                                                                      0.2      0.15     0.3                                       Spreading speed (mm/sec)                                                                        6        6        6                                         Acrylate adhesive film                                                                          0.15     None     None                                      (Wet film thickness)                                                          Active Agent Penetration                                                      through isolated rat skin.                                                    Penetration Flux (microgram/                                                                    1.3      4.5      3.2                                       cm.sup.2 /hr)                                                                 Steady state flux 10       12       8.6                                       (microgram/cm.sup.2 /hr)                                                      ______________________________________                                    

EXAMPLE 9-12 Bopindolol Pharmaceutical Compositions

The following compositions are made in analogous manner to Example 2.

    __________________________________________________________________________    Example          9    10    11   12                                           __________________________________________________________________________    Bopindolol hydrogen malonate                                                                   1.275                                                                            g 1.275                                                                            g  --   --                                           Bopindolol free base                                                                           --   --    1.0                                                                              g 1.0                                                                              g                                         PAM Amine polymer RL                                                                           1.225                                                                            g 1.225                                                                            g  --   --                                           PM Amine polymer E                                                                             --   --    2.665                                                                            g 2.665                                                                            g                                         Polyoxyethylene-(10) oleyl                                                                     --   0.25                                                                             g  1.335                                                                            g --                                           ether                                                                         Polyethylene-(9) glycol                                                                        --   --    --   1.335                                                                            g                                         glyceryl cocoate                                                              Azone            2.5                                                                              g 2.25                                                                             g  --   --                                           Solvent          CH.sub.2 Cl.sub.2                                                                  CH.sub.2 Cl.sub.2                                                                   CH.sub.3 OH                                                                        CH.sub.3 OH                                  Solvent amount (g/g dry film)                                                                  1.0  1.0   4.0  4.0                                          Thickness of wet film (mm)                                                                     0.25 0.25  0.3  0.3                                          Spreading speed (mm/sec)                                                                       6    6     6    6                                            Acrylate adhesive film                                                                         None None  None None                                         (Wet film thickness)                                                          Active Agent Penetration through                                              isolated rat skin.                                                            Penetration Flux (microgram/                                                                   1.7  4.0   11.1 8.6                                          cm.sup.2 /hr)                                                                 Steady Rate flux 5.7  12.5  59.0 33.0                                         (microgram/cm.sup.2 /hr)                                                      __________________________________________________________________________

EXAMPLE 13-16 Ketotifen Pharmaceutical Compositions

The following compositions are made in analogous manner to Example 2.

    __________________________________________________________________________    Example          13   14    15   16                                           __________________________________________________________________________    Ketotifen hydrogen fumarate                                                                    0.5                                                                              g 0.5                                                                              g  --   --                                           Ketotifen free base                                                                            --   --    1.0                                                                              g 1.0                                                                              g                                         PAM Amine Polymer RL                                                                           --   --    2.0                                                                              g 2.0                                                                              g                                         PM Amine Polymer E                                                                             2.5                                                                              g 2.5                                                                              g  --   --                                           Polyoxyethylene (20)                                                                           --   --    --   2.0                                                                              g                                         sorbitan monooleate                                                           Polyethylene glycol 300                                                                        --   2.0                                                                              g  --   --                                           Polyethylene glycol-(7)                                                                        2.0                                                                              g --    2.0                                                                              g --                                           glyceryl cocoate                                                              Solvent          Acetone                                                                            Acetone                                                                             Acetone                                                                            Acetone                                      Thickness of wet film (mm)                                                                     0.2  0.2   0.2  0.2                                          Spreading speed (mm/sec)                                                                       6    6     6    6                                            Acrylate adhesive film                                                                         None None  None None                                         Active Agent Penetration                                                                       6.8  8.5   4.0  2.8                                          through isolated rat skin                                                     Penetration Flux (microgram/                                                  cm.sup.2 /hr)                                                                 Steady state flux                                                                              10.0 15.0  18.0 12.0                                         (microgram/cm.sup.2 /hr)                                                      __________________________________________________________________________

EXAMPLE B

In analogous manner to that described in Example A a pharmaceuticalcomposition is made without an acrylate adhesive layer. The drug matrixis based on an elastomer.

    ______________________________________                                                              B1     B2                                               ______________________________________                                        Weight g/m.sup.2        80       79                                           Tizanidine hydrochloride                                                                              15.00    14.81                                        mg/10 cm.sup.2                                                                Tizanidine free base    17.16    16.95                                        Acrylate synthetic resin                                                                              50       50                                           parts by weight                                                               PAM Amine polymer RL    50       --                                           parts by weight                                                               PM Amine polymer E               50                                           parts by weight                                                               Polyethylene glycol 400 2%       2%                                           In vitro data Active agent release mg/10 cm.sup.2                             2 hour                  14.36    19.48                                        4 hour                  15.78    22.22                                        8 hour                  17.33    24.03                                        24 hour                 22.57    28.98                                        ______________________________________                                    

EXAMPLE C Bopindolol Penetration from Solutions

Solutions of the following compositions are made up and the penetrationrate observed.

    ______________________________________                                        Constituents       C1       C2     C3                                         ______________________________________                                        Bopindolol hydrogen malonate                                                                     --       1.0 g  1.0 g                                      Bopindolol (free base)                                                                           1.0 g    --     --                                         Ethanol (ml)       0.049    0.049  0.048                                      Acetone (ml)       0.049    --     --                                         Polyethylene glycol (7)                                                                          0.003    0.003  --                                         glyceryl cocoate                                                              Water              --       --     0.048                                      Azone              --       --     0.048                                      Active agent Penetration                                                      through the rat skin                                                          (microgram/cm.sup.2 /hr)                                                      Flux               0.8      0.3    6.0                                        Steady state Flux  --       --     5.8                                        ______________________________________                                    

What we claim is:
 1. A pharmaceutical composition for the transdermalsystemic administration of an active agent comprising, in the form of anadhesive plaster or patch, a cover layer and a drug reservoir containinga homogeneous dispersion of active agent particles or a solution ofactive agent in a polymer matrix wherein said active agent is bopindololin the free base or pharmaceutically acceptable acid addition salt form.2. The pharmaceutical composition of claim 1 wherein said compositionhas a skin penetration flux of said active agent of at least 0.3micrograms per cm² per hour when measured through isolated rat skin. 3.The pharmaceutical of claim 1 wherein said skin penetration flux is atleast 0.8 micrograms per cm² per hour.